Process for the preparation of fluorinated heterocyclic compounds

ABSTRACT

A method of fluorinating a heterocyclic organic compound comprises the step of reacting a heterocyclic compound with elemental fluorine in the presence of another halogen. The reaction may be conducted in the presence of a base.

The present invention relates to the preparation of halogenatedcompounds, in particular, halogenated heterocyclic compounds. Moreparticularly, the invention relates to the fluorination of heterocycliccompounds.

The preparation of halogenated heterocycles has received a great deal ofattention due to the many synthetic and industrial processes in whichsuch substrates are employed, for example, in the pharmaceutical, plantprotection and dye industries.

Few methods are available for the introduction of a fluorine atom at the2- and/or 6-positions of pyridine. Traditionally, routes to2-fluoropyridines have been based on multi-step BalzSchieman typedecompositions of pyridine diazonium tetrafluoroborate salts. Halogenexchange processes involving the reaction of a fluoride ion source, suchas SbF₅, KF, HF, etc, with a chlorinated pyridine at elevatedtemperatures have frequently been used to prepare fluoropyridines. Theelectrochemical fluorination of pyridine in the presence of a source offluoride ion gave 2-fluoropyridine in only 22% yield. With xenondifluoride, pyridine gave a mixture of fluoropyridines and, also, cesiumfluorooxysulfate reacts with pyridine at room temperature in ether togive 2-fluoropyridine in 61% yield.

The preparation of related fluorine-containing heterocycles such as2-fluoroquinoline may be accomplished by similar methodology, ie halogenexchange processes, fluorodediazotisation. etc.

A method for the direct fluorination of organic compounds is disclosedin U.S. Pat. No. 2013030. However, the technique is primarily directedtowards non-heterocyclic derivatives and, in any event, is subject tounwanted side reactions and, as a consequence, yields of desiredproducts are generally poor, and the material obtained is in a low stateof purity. Preparations of 2-fluoropyridines by direct reaction withelemental fluorine have also been reported in U.S. Pat. No. 4786733. Inthis case, the reactions are kinetically competitive with side chainfluorination and, therefore, yields of the desired 2-fluoropyridines areagain low. In addition, the reported reaction of elemental fluorine withquinoline results in predominant fluorination of the annulated aromaticring and extensive fragmentation of the hetero ring. Surprisingly, ithas now been found that heterocyclic compounds can be selectivelyfluorinated by elemental fluorine when another halogen is present in thereaction medium.

According to the present invention, there is provided a method ofpreparing a heterocyclic organic compound having at least one fluorinesubstituent in the heterocyclic ring, the method comprising the step ofreacting a heterocyclic compound with elemental fluorine in the presenceof at least one of chlorine, bromine, iodine and an interhalogencompound.

Examples of interhalogen compounds are iodine monobromide and iodinemonochloride.

The heterocyclic compound which is fluorinated by the method of thepresent invention may be a nitrogen-containing heterocyclic compound.The heterocyclic compound may include a five- or six-membered ring whichmay contain optional sustituents. The ring may be attached or fused toanother one or more rings which may or may not be heterocyclic.

The heterocyclic compound preferably includes a six-membered aromaticring containing one or more nitrogen atoms such as pyridine or a relatedheterocycle such as pyrimidine, pyridazine or triazine, or a relatedbenzo-fused heterocycle such as quinoline, isoquinoline, quinoxaline orquinoazoline, or a bi-or poly-cyclic compound such as bipyridine.

The positions of the ring or rings of the heterocyclic compoundfluorinated by the method according to the present invention which arenot occupied by heteroatoms may carry substituents. Thus, where theheterocycle is pyridine it may carry substituents at from one to fivering positions. Where the heterocycle is a pyrimidine it may carrysubstituents at from one to four ring positions. Where the heterocycleis quinoline or isoquinoline it may carry substituents at from one tosix ring positions. Optional ring substituents (which may themselvescontain optional substituents) may be independently selected from alkyl,alkoxy, halogen, --CN, --OH, --NO₂, --NH₂, NHalkyl, --N(alkyl)₂,--NHCOalkyl, --COOalkyl, --COOH, --COalkyl, --CONH₂, --CONH(alkyl),--CON(alkyl)₂, --COY, --CY₃ ¹ and SO₂ Y² wherein

    Y is --H, --F, --Cl, --Br, alkyl, --OH or --Oalkyl

    Y.sup.1 is --F or --Cl

    Y.sup.2 is --F, --Cl, --Br, --NH.sub.2, --NHalkyl, or --N(alkyl).sub.2.

In each of these substituents alkyl is preferably C₁₋₄ -alkyl, alkoxy ispreferably C₁₋₄ -alkoxy and halogen is preferably --F or --Cl.

In each of these substituents alkyl is preferably C₁₋₄ -alkyl, alkoxy ispreferably C₁₋₄ -alkoxy and halogen is preferably --F or --Cl.

When the aromatic compound is pyridine, it is preferably unsubstituted,monosubstituted or disubstituted. When pyridine is monosubstituted, itis preferably substituted in the 4-position. When pyridine isdisubstituted, it is preferably substituted in the 2- and 4-position.

Preferred substituents for the heterocyclic compound are selected from--OH, --CN, --NO₂, NHCOCH₃, --OCH₃, --COOCH₃, --COOH, --COCH₃, --CH₃,--F, --Cl, --Br, --CF₃ and --CONH₂ and combinations thereof.

All hydrogens on carbon atoms bonded to the heteroatom may besubstituted by fluorine if the stoichiometry of the experiment isaltered. For instance, two fluorine atoms may be selectively introducedinto heterocyclics as, for instance, pyridine gave 2,6-difluoropyridinewhen two equivalents each of fluorine and, halogen were used. By asimilar process, quinoxaline gave 2,3-difluoroquinoxaline and pyrimidinegave difluorinated pyrimidines.

In a preferred method according to the present invention, a base isadded to the reaction medium. The base may be an organic base such astriethylamine or an inorganic base such as sodium fluoride. It has beensurprisingly found that this addition of a base to the reaction mediumgives a significantly higher conversion of starting heterocyclic tofluorinated products in a given time.

Examples of fluorinations which may be carried out by the method of thepresent invention are given in FIG. 1 of the accompanying drawings. Thegroups R₁ to R₄ are independently selected from hydrogen and the varioussubstituents for hydrogen specified above.

FIG. 2 of the accompanying drawings gives examples of fluorinations bythe method of the present invention in which two fluorine atoms areintroduced into the heterocycle. Again the groups are R₁ to R₄ areindependently selected from hydrogen and the various substituents forhydrogen specified above.

Examples of organic bases which may be used are triethylamine,tributylamine and N-methylpiperidine. Examples of inorganic bases aresodium fluoride and potassium fluoride.

The ratio of base to the heterocyclic compound may be varied within widelimits although it is preferred that the molar ratio is in the range 0.2to 8.0:1, especially 1.0 to 1.4:(base: heterocyclic compound).

The method according to the present invention may be carried out bypassing fluorine gas into a liquid which contains the heterocycliccompound, halogen and, if used, base. The reaction may be carried out inthe vessel in which the liquid is present or alternatively a flow-streamof the liquid may be contacted with the gaseous flow of fluorine incountercurrent fashion. The liquid may comprise a common inert, organicsolvent such as acetonitrile or a fluorinated organic liquid such as afluorinated alkane (eg CF₂ ClCFCl₂), a perfluoroalkane,perfluorodecalin, a fluorinated ether, a perfluorinated ether, or apartly fluorinated alkane.

The process may be carried out at a temperature from -20° C. to 80° C.,preferably at a temperature from -10° C. to 30° C. and especially at atemperature from -5° C. to 25° C.

The fluorine gas is preferably diluted before use by mixing with aninert gas such as nitrogen or helium. The concentration of fluorine ispreferably from 1% to 50% by volume, more preferably from 2% to 25% andespecially from 5% to 15%.

The ratio of fluorine to heterocyclic compound may be varied within widelimits although it is preferred that the molar ratio of fluorine toaromatic compound is from 0.5:1 to 6:1 and especially from 1:1 to 4:1.Use of a higher ratio for fluorine to heterocyclic compound ensures thatmore than one fluorine atom can be selectively introduced into theheterocyclic compound.

When fluorination is complete, the fluorinated products may be isolatedby purging the reaction mixture with nitrogen to remove any residualfluorine gas, followed by dilution with excess water and neutralisation,followed by extraction into a suitable solvent, followed bydistillation. The fluorinated heterocyclic products may be separated byfractional distillation, chromatography or by crystallisation from asuitable solvent.

When fluorination is complete, the fluorinated products may be isolatedby purging the reaction mixture with nitrogen to remove any residualfluorine gas, followed by dilution with excess water and neutralisation,followed by extraction into a suitable solvent, followed bydistillation. The fluorinated heterocyclic products may be separated byfractional distillation, chromatography or by crystallisation from asuitable solvent.

The method according to the present invention offers a simple,convenient route to the preparation of fluorinated heterocycles directlyfrom the parent heterocycle and elemental fluorine. Thus, thepreparation of chlorinated heterocycles for halogen exchange reactionsor aminated heterocycles for dediazotisation reactions is not necessaryin the method of the present invention. Thus, the present method offersa simple one-step procedure for the preparation of fluorinatedheterocycles.

The introduction of a base into the reaction mixture ensures rapidconversion of starting material to product and is, therefore, aparticularly advantageous embodiment of the present invention.

The method according to the present invention is further illustratedwith reference to the following examples:

Example 1:Preparation of 2-fluoropyridine

A solution containing pyridine (9.5 g, 120 mmol) and iodine (30.0 g, 118mmol) in Arklone (Trade Mark) (CFCl₂ --CFCl₂) (150 ml) was placed in afluorination apparatus fitted with a drying tube filled with soda lime.Elemental fluorine (165 mmol) as a 10% mixture in dry nitrogen was thenpassed through the stirred solution using narrow bore PTFE tubing at ca.40 ml/min. After the fluorine had been added, the solution was pouredinto 10% aqueous sodium metabisulfite solution (300 ml), neutralisedwith solid sodium bicarbonate and continuously extracted withdichloromethane. The organic extracts were dried and evaporated to ayellow oil which was identified as 2-fluoropyridine (6.5 g, 56%) in >95%purity by GC; (δ_(H) (200 MHz, CDCl₃, Me₄ Sl) 6.9 ppm (1H, m), 7.2 (1H,m), 7.8 (1H, m), 8.2 (1H, m); (C (50 MHz, CDCl₃, Me₄ Si) 109.4 ppm (d, ²J_(C-F) 37.1, 3-C), 121.3 (d, ⁴ J_(C-F) 4.2, 5-C), 141.2(d, ³ J_(C-F)7.7, 4-C), 147.5 (d, ² J_(C-F) 14.5, 6-C), 163.5 (d, ¹ J_(C-F) 237.4,2-C); (δ_(F) (235 MHz, CDCl₃, CFCl₃)-67.9 ppm (s, 2-F); m/z (E1+) 97(M⁺, 100%), 70 (68), 69 (12), 57 (18), 50 (29), 39 (22).

Example 2: Preparation of 4.7-dichloroquinoline without use of base

A solution containing 4,7-dichloroquinoline (1.0 g, 5 mmol) and iodine(1.28 g, 5 mmol) in CF₂ ClCFCl₂ (30 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (7 mmol) as a 10% mixture by volume in dry nitrogen was thenpassed through the stirred solution using narrow bore PTFE tubing at ca.15 ml/min. After the fluorine had been added, the solution was pouredinto 10% aqueous sodium metabisulfite solution (30 ml) and extractedwith dichloromethane. The organic extracts were dried and evaporated toan oil (0.98 g). GC/MS analysis showed a 34% conversion of startingmaterial. Column chromatography on silica gel with dichloromethane aseluant gave 2-fluoro-4,7-dichloroquinoline (0.33 g, 87%) as whitecrystals; other data were the same as that described in the followingreaction.

Example 3: Fluorination of 4.7-dichloroquinoline with use of base

A solution containing 4,7-dichloroquinoline (1.0 g, 5 mmol), iodine(1.28 g, 5 mmol) and triethylamine (0.51 g, 5.1 mmol) in CF₂ ClCFCl₂ (30ml) was placed in a fluorination apparatus fitted with a drying tubefilled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture indry nitrogen was then passed through the stirred solution using narrowbore PTFE tubing at ca. 15 ml/min. After the fluorine had been added,the solution was poured into 10% aqueous sodium metabisulfite solution(30 ml) and extracted with dichloromethane. The organic extracts weredried and evaporated to a brown oil (1.06 g). GC/MS analysis showed a69% conversion of starting material. Column chromatography on silica gelwith dichloromethane as eluant gave 2-fluoro-4,7-dichloroquinoline (0.66g, 88%) as white crystals; m.p. 105°-106° C. (vacuum sublimation oilbath temp. 60° C./<1 mmHg); R_(F) 0.72; (Found: C, 49.7; H, 1.7;N, 6.3.C₉ H₄ CI₂ FN requires: C, 50.0; H, 1.85; N, 6.5%); δ_(H) (400 MHz; CDCI₃; Me₄ Si) 7.20 ppm (1H, d, J_(H3),F 2.4,H-3),7.58 (1H, d d, J_(H5),H6,9.0 J_(H6),H8 2.2, H-6), 7.95 (1H, d, J_(H6),H8 2.0, H-8), 8.13 (1H, d,J_(H5),H6 9.2, H-5); δF (235MHz; CDCI₃ ; Me₄ Si)-60.0ppm (s); δ_(C) (100MHz, CDCI₃, Me₄ Si)110.38 (d, ² J 45.8, C-3), 123.6 (d,⁴ J 2.3, C-4a),125.5 (s, C-6), 127.6 (d, ⁵ J 1.2, C-5), 128.1 (d, ⁴ J 2.6, C-8), 137.9(s, C-7), 146.4 (d, ³ J 24.6, C-4), 146.6 (d, ³ J 18.5, C-8a), 160.9 (d,¹ J 244.1, C-2); m/z (E1+) 215 (M⁺, 100%), 217 (61, M⁺ +2), 219 (11, M³⁰+4), 182(14), 180 (40), 145 (18).

Example 4: Fluorination of 3-bromoquinoline with use of base

A solution containing 3-bromoquinoline (1.0 g, 4.8mmol), iodine (1.22g,4.8mmol) and triethylamine (0.48 g, 4.8 mmol) in CF₂ ClCFCl₂ (30 ml) wasplaced in a fluorination apparatus fitted with a drying tube filled withsoda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogenwas then passed through the stirred solution using narrow bore PTFEtubing at ca. 15 ml/min. After the fluorine had been added the solutionwas poured into 10% aqueous sodium metabisulfite solution (30 ml) andextracted with dichloromethane. The organic extracts were dried andevaporated to a brown oil (0.95 g). GC/MS analysis showed a 56%conversion of starting material. Column chromatography on silica gelwith dichloromethane as eluant gave 2fluoro-3-bromoquinoline (0.52g,85%); mp 75°-76° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg)as white needles; R_(F) 0.69 (CH₂ Cl₂); (Found: C, 47.5; H, 2.1; N, 6.2.C₉ H₅ NBrF requires: C, 47.8; H, 2.2; N, 6.2%); δ_(H) (400 MHz, CDCl₃,Me₄ Si) 7.55 ppm (1H, d d, J_(H5),H6 =J_(H6),H7 8.0, H-6), 7.74 (1H, d dd, J_(H7),H8 8.4, J_(H6),H7 7.2, J_(H5),H7 1.2, H-7), 7.76 (1H,d,J_(H5),H6 8.0, H-5), 7.91 (1H, d d, J_(H7),H8 8.4, J_(H6),H8 0.8, H-8),8.42 (1H, d, J_(H4),F 8.4, H-4); δ_(C) (100 MHz, CDCl₃, Me₄ Si) 104.0(d, ² J 43.2, C-3), 126.6 (s, C-6), 127.0 (d, ⁴ J 2.7, C-8), 128.0 (d, ⁵J 1.9, C-5) 128.0 (d, ⁴ J 2.2, C-4a), 130.9 (d, ⁵ J 1.1, C-7), 143.5 (d,³ J, 3.7, C-4), 144.2 (d, ³ J 15.1, C-8a), 157.3 (d, ¹ J 238.1, C-2);δ_(F) (235 MHz, CDCl₃, CFCl₃) -60.8ppm (s); m/z (E1+) 225 (M⁺, 100%),227 (M⁺, 74), 146 (56), 126 (23), 101 (18), 75 (14).

Example 5: Fluorination of 4-Chloroquinoline

A solution containing 4-chloroquinoline (1.0 g, 6 mmol), iodine (l.55 g,6 mmol) and triethylamine (0.60 g, 6 mmol) in CF₂ ClCFl₂ (30 ml) wasplaced in a fluorination apparatus fitted with a drying tube filled withsoda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogenwas then passed through the stirred solution at room temperature usingnarrow bore PTFE tubing at 20 ml/min. After the fluorine had been addedthe solution was poured into 10% aqueous sodium metabisulfite solution(30 ml) and extracted with dichloromethane. The organic extracts weredried and evaporated to a brown oil (1.01 g). GC/MS analysis showed a76% conversion of starting material. Column chromatography on silica gelwith dichloromethane as eluant gave 2 fluoro-4-chloroquinoline (0.76 g,90%); m.p 60°-61° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg)as white needles; R_(F) 0.78 (CH₂ CI₂); (Found C, 59.7;H, 2.9; N, 7.6.C₉ H₅ NClF requires: C, 59.5; H, 2.75; N, 7.7%); δ_(H) (400 MHZ, CDCl₃,Me₄ Si) 7.20 ppm (1H, d, J_(H),3,F 2.4, H-3), 7.62 (1H, d d d, J_(H5),H6=J_(H6),H7 7.4, J_(H6),H8 1.2, H-6), 7.78 (1H, d d d, J_(H6),H7=J_(H7),H8 7.8, J_(H5),H7 1.2, H-7), 7.96 (1H, d, J_(H7),H8 8.4, H-8),8.19 (1H, d, H_(H5),H6 8.4, H-5); δ_(F) (235 MHz, CDCl₃, CFCl₃) -61.5 pm(s); δ_(C) (100 MHz, CDCl₃, Me₄ Si) 110.2 ppm (d, ² J 45.8, C-3), 124.2(d, ⁵ J 0.8, C-5), 125.1 (d,⁴ J 2.6, C-4a), 127.0 (d ⁶ J 2.7, C-6),128.5 (d, ⁴ J 1.5, C-8), 131.6 (s, C-7), 145.9 (d, ³ J 18, C-8a), 146.6(d, ³ J 12.5, C-4), 160.2 (d, ¹ J 242.3, C-2); m/z (E1⁺) 183 (M⁺, 26%),181 (M⁺, 100%), 146 (35), 126 (15), 75 (12), 50 (11).

Example 6: Fluorination of 6-Chloroquinoline

A solution containing 6-chloroquinoline (1.0 g, 6.1 mmol), iodine (1.55g, 6.1 mmol) and triethylamine (0.62 g, 6.2 mmol) in CF₂ ClCFCl₂ (30 ml)was placed in a fluorination apparatus fitted with a drying tube filledwith soda lime. Elemental fluorine (7 mmol) as a 10% mixture in drynitrogen was then passed through the stirred solution using narrow borePTFE tubing at ca. 15 ml/min. After the fluorine had been added thesolution was poured into 10% aqueous sodium metabisulfite solution (30ml) and extracted with dichloromethane. The organic extracts were driedand evaporated to a brown solid (1.03 g). GC/MS analysis showed a 79%conversion of starting material. Column chromatography on silica gelwith dichloromethane as eluant gave 2-fluoro-6-chloroquinoline (0.82 g,93%), R_(F) 0.78 (CH₂ Cl₂); δ_(H) (400 MHz CDCl₃, Me₄ Si) 7.12 ppm (1H,d d, J_(H3),H4 8.8, J_(H3),F 2.8, H-3), 7.67 (1H, d d, J_(H7),H8 9.2,J_(H5),H7 2.4, H-7), 7.82 (1H, d, J_(H5),H7 2.4, H-5), 7.87 (1H, d,J_(H7),H8 9.0, H-8), 8.16 (1H, d d, J_(H3),H4 =J_(H4),F 8.8, H-4);δ_(C)(100 MHz, CDCl₃, Me₄ Si) 111.1 ppm (d, ² J 42.3, C-3), 126.3 (s, C-5),127.3 (s, C-4a), 129.6 (s, C-8), 131.4 (s, C-7), 131.9 (s, C-6) 141.0(d,³ J 9.9, C-4), 144.1 (d ³ J 16.8, C-8a), 161.2 (d, ¹ J 243.8, C-2);δ_(F) (235 MHz, CDC1₃, CFCl₃) -61.5 ppm (s); m/z (E1+) 181 (M⁺, 100%),183 (M⁺, 32), 146 (34), 126 (11).

Example 7: Fluorination of Phenanthridine with use of base

A solution containing phenanthridine (1.0 g, 5.6 mmol), iodine (1.4 g,5.6 mmol) and triethylamine (0.56 g, 5.6 mmol) in CF₂ ClCFCl₂ (30 ml)was placed in a fluorination apparatus fitted with a drying tube filledwith soda lime. Elemental fluorine (7 mmol) as a 10% mixture in drynitrogen was then passed through the stirred solution using narrow borePTFE tubing at ca. 15 ml/min. After the fluorine had been added thesolution was poured into 10% aqueous sodium metabisulfite solution (30ml) and extracted with dichloromethane. The organic extracts were driedand evaporated to a brown oil (0.92 g). GC/MS analysis showed a 53%conversion of starting material. Column chromatography on silica gelwith dichloromethane as eluant gave 6-fluoro-phenanthridine (0.39 g,67%), R_(F) 0.78 (CH₂ Cl₂); δ_(H) (400 MHz, CDCl₃, Me₄ Si) 7.61 ppm (1H,d d d, J_(H1),H2 =J_(H2),H3 =7.8, J_(H2),H4 1.2, H-2), 7.69 (2H, m, H-3and H-9), 7.88 (1H, d d d, J_(H7),H8 8.4, J_(H8),H9 7.2, J_(H8),H10 1.4,H-8), 7.97 (1H, d d, J_(H3),H4 8.0, J_(H2),H4 1.2, H-4), 8.21 (1H, d d,J_(H9),H10 8.0, J_(H8),H10 1.4, H-10) 8.45 (1H, d d, J_(H1),H2 8.0,J_(H1),H3 0.8, H-1), 8.52 (1H, d d, J_(H7),H8 8.4 J_(H7),H9 1.2, H-7);δ_(F) (376 MHz, CDCl₃, CFCl₃), 68.2 ppm (s); δ_(C) (100 MHz, CDCl₃, Me₄Si) 117.3 ppm (d, ² J 35.1, C-6a), 122.2 (d, ³ J 3.8, C-7), 122.2 (s,C-1), 123.9 (d, ⁴ J 1.9, C-10b), 124.2 (s, C-10), 126.5, (d, ⁶ J 2.3,C-2), 127.9 (s, C-9), 128.7 (d, ⁴ J 1.6, C-4), 129.4 (s, C-3), 132.1 (s,C8), 136.5 (d, ³ J 7.2, C-10a), 141.5 (d, ³ J 17.9, C-4a), 158.1 (d, ¹ J248.7, C-6); m/z (E1⁺) 197 (M⁺, 100%).

Example 8: Fluorination of 4-ethyl-pyridine

A solution containing 4-ethylpyridine (12.8 g, 120 mmol) and iodine(30.5 g, 120 mmol) in CF₂ ClCFCl₂ (150 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (165 mmol) as a 10% mixture in dry nitrogen was then passedthrough the stirred solution using narrow bore PTFE tubing at ca. 40ml/min. After the fluorine had been added the solution was poured into10% aqueous sodium metabisulfite solution (300 ml), neutralised withsolid sodium bicarbonate and extracted with dichloromethane. The organicextracts were dried and evaporated to a yellow oil (9.54 g) whichcontained ethlpyridine (78 % conversion), 2-fluoropyridine and otherminor products by GC/MS. The oil redissolved in dichloromethane andwashed with 2N HCI solution, dried (MgSO₄) and evaporated to a clear oilto give 2-fluoro-4-ethylpyridine in >95% purity (6.3 g, 54% based on 78%conversion); δ_(H) (200 MHz, CDCl₃, Me₄ Si) 1.26 ppm (3H, t, J 7.6,CH₃), 2.69 (2H, q, J 7.6, CH₂), 6.75 (1H, s, H-3), 7.02 (1H, d m, J 5.1,H-5), 8.09 (1H, d, J 5.1, H-6); δ_(C) (50 MHz, CDCl₃, Me₄ Si) 14.1 ppm(s, CH₃), 28.2 (d, ⁴ JC-F 2.7, CH₂), 108.5 (d, ² J_(C-F) 36.5, C-3),121.3 (d, ⁴ J_(C-F) 3.9, C-5), 147.3 (d, ³ J_(C-F) 15.2, C-6), 159.3 (d,³ J_(C-F) 7.8, C-4), 164.2 (d, ¹ J_(C-F) 236.3, C-2); δ_(F) (235 MHz,CDCl₃, CFC1₃) 69.9 ppm (s); m/z (E1+125 (M⁺, 100%), 110 (47), 97 (15),83 (13).

Example 9: Fluorination of quinoline

A solution containing quinoline (10.6 g, 82.5 mmol) and iodine (21.0 g,82.5 mmol) in CF₂ ClCFCl₂ (150 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (165 mmol) as a 10% mixture in nitrogen was then passed throughthe stirred solution using a narrow bore PTFE tubing at ca. 40 ml min⁻¹.After the fluorine had been added the solution was poured into aqueoussodium metabisulphite solution (300 ml), neutralised with sodiumbicarbonate and extracted with dichloromethane. The organic extractswere dried (MgSO₄) and evaporated to leave an oil (7.2 g). Distillationafforded 2-fluoroquinoline (6.5 g, 54%) as a pale yellow oil; b.p ³⁰.134-136° C. (lit., b.p³⁰ 133° C.); δ_(H) (400 MHz; CDCl₃ ; Me₄ Si) 7.05ppm (1H, d d, J_(H3),H4 8.8, J_(H3),F 2.8, H-3), 7.51 (1H, d d d,J_(H5), H6 8.0, J_(H6),H7 6.8, J_(H6),H8 0.8, H-6), 7.71 (1H, d d d,J_(H7),H8 8.0, J_(H6),H7 7.6, J_(H5),H7 1.2, H-7), 7.81 (1H, d,J_(H5),H6 8.0, H-5), 7.94 (1H, d, J_(H7),H8 8.4, H-8), 8.20 (1H, d d,J_(H3),H4 =J_(H4),F 8.4, H-4); δ_(F) (250 MHz; CDCl₃ ; Me₄ Si) -63.2ppm; δ_(C) (100 MHz, CDC1₃, Me₄ Si) 110.0 ppm (d, ² J 42.1, C-3), 126.1(d, ⁴ J 2.6, C-8), 126.8 (d, ⁴ J 1.9, C-4a), 127.5 (s, C-6), 128.0 (d, ⁵J 1.2, C-5), 130.6 (d, ⁵ J 0.8, C-7), 141.9 (d, ³ J 9.9, C-4), 145.7 (d,³ j 16.7, C-8a), 161.1 (d ¹ J 240.5, C-2); m/z (E1+) 147 (M⁺, 100%).

Example 10: Fluorination of 3-bromoquinoline without use of base

A solution containing 3-bromoquinoline (1.0 g, 4.8 mmol) and iodine(1.22 g, 4.8 mmol) in CF₂ ClCFCl₂ (30 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (5 mmol) as a 10% mixture in dry nitrogen was then passedthrough the stirred solution using narrow bore PTFE tubing at ca. 15ml/min. After the fluorine had been added the solution was poured into10% aqueous sodium metaisulfite solution (30 ml) and extracted withdichloromethane. The organic extracts were dried and evaporated to abrown oil (0.92 g). GC/MS analysis showed a 43% conversion of startingmaterial. Column chromatography on silica gel with dichloromethane aseluant gave 2-fluoro-3-bromoquinoline (0.35 g, 74%); m.p. 75°-76° C.(vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles;R_(F) 0.69 (CH₂ Cl₂); (Found: C, 47.5; H, 2.1; N, 6.2. C₉ H₅ NBrFrequires: C, 47.8; H, 2.2; N, 6.2%); δ_(H) (400 MHz, CDCl₃, Me₄ Si) 7.55ppm (1H, d d, J_(H5),H6 =J_(H6),H7 8.0, H-6), 7.74 (1H, d d d, J_(H7),H88.4, J_(H6),H7 7.2, J_(H5),H7 1.2, H-7), 7.76 (1H, d, J_(H5),H6 8.0,H-5), 7.91 (1H, d d, J_(H7),H8 8.4, J_(H6),H8 0.8, H-8), 8.42 (1H, d,J_(H4),F 8.4, H-4); δ_(C) (100 MHz, CDCl₃, Me₄ Si) 104.0 (d, ² J 43.2,C-3), 126.6 (s, C-6), 127.0 (d, ⁴ J 2.7, C-8), 128.0 (d, ⁵ J 1.9, C-5)128.0 (d, ⁴ J 2.2, C-4a), 130.9 (d, ⁵ J 1.1, C-7), 143.5 (d,³ J 3.7,C-4), 144.2 (d, ³ J15.1, C-8a), 157.3 (d ¹ J 238.1, C-2); δ_(F) (235MHz, CDCl₃, CFCl₃) -60.8 ppm (s); m/z (E1+) 225 (M⁺, 100%), 227 (M⁺,74), 146 (56), 126 (23), 101 (18), 75 (14).

Example 11: Fluorination of 4-chloro-7-trifluoromethylquinoline

A solution containing 4-chloro-7-trifluoromethyl-quinoline (1.0 g, 4.3mmol) and iodine (1.1 g, 4.3 mmol in CF₂ ClCFCl₂ (30 ml) was placed in afluorination apparatus fitted with a drying tube filled with soda lime.Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was thenpassed through the stirred solution using narrow bore PTFE tubing at ca.15 ml/min. After the fluorine had been added the solution was pouredinto 10% aqueous sodium metablsuifite solution (30 ml), neutralised withsolid sodium bicarbonate and extracted with dichloromethane. The organicextracts were dried and evaporated to a yellow solid (1.09 g). GC/MSanalysis showed a 5% conversion of starting material. Columnchromatography on silica gel with dichloromethane as eluant gave2-fluoro-4-chloro-7-trifluoromethyl-quinoline (0.05 g, 86%); m.p.94°-95° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as whiteneedles; R_(F) 0.69 (CH₂ Cl₂); (Found C, 47.7; H, 1.3; N, 5.5. C₁₀ H₄NCIF₄ requires; C, 48.1; H, 1.6; N, 5.6%); δ_(H) (400 MHz, CDCl₃, Me₄Si) 7.32 ppm (1H, d, J_(H),F 2.4, H-3), 7.79 (1H, d d, J_(H5),H6 8.8,J_(H6),H8 1.6, H-6), 8.23 (1H, m, H-8), 8.32 (1H, d, J_(H5),H6 8.8,H-5); δ_(C) (50 MHz, CDCl₃, Me₄ Si) 112.3 ppm (d, ² J_(CF) 45.5, C-2),122.9 (m, C-6), 123,4 (q, ¹ J_(CF) 272.7, CF₃), 125.6 (s, C-5), 126.2(m, C-8), 126.7 (s, C-4a), 133.4 (q, ² J_(CF) 33.2, C-7), 145.2 (d, ³J_(CF) 18.7, C-8a), 146.7 (d, ³ J_(CF) 12.9, C-4), 160.9 (d, ¹ J_(CF)245.3, C-2); δ_(F) (235 MHz, CDCl₃, CFCl₃) -55.0 ppm (1F, s, F-2), -59.2(3F, s, CF₃); m/z (E1⁺) 249 (M⁺, 100%), 251 (M⁺, 33), 230 (26), 214(18), 201 (11), 199 (33), 194 (12), 145(26), 99 (19).

Example 12: Fluorination of Phenanthridine without use of base

A solution containing phenanthridine (1.0 g, 5.6 mmol) and iodine (1.4g, 5.6 mmol) in CF₂ ClCFCl₂ (30 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (7 mmol) as a 10% mixture in dry nitrogen was then passedthrough the stirred solution using narrow bore PTFE tubing at ca. 15ml/min. After the fluorine had been added the solution was poured into10% aqueous sodium metabisulfite solution (30 ml) and extracted withdichloromethane. The organic extracts were dried and evaporated to anorange oil (0.91 g). GC/MS analysis showed a 17% conversion of startingmaterial. Column chromatography on silica get with dichloromethane aseluant gave 6-fluoro-phenanthridine (0.09 g, 48%); R_(F) 0.78 (CH₂ Cl₂);δ_(H) (400 MHz, CDCl₃, Me₄ Si) 7.61 ppm (1H, d d d, J_(H1),H2 =J_(H2),H3=7.8, J_(H2),H4 1.2, H-2), 7.69 (2H, m, H-3 and H-9), 7.88 (1H, d d d,J_(H7),H8 8.4, J_(H8),H9 7.2, J_(H8),H10 1.4, H-8), 7.97 (1H, d d,J_(H3),H4 8.0, J_(H2),H4 1.2, H-4), 8.21 (1H, d d, J_(H9),H10 8.0,J_(H8),H10 1.4, H-10 8.45 (1H, d d, J_(H1),H2 8.0, J_(H1),H3 0.8, H-1),8.52 (1H, d d, J_(H7),H8 8.4, J_(H7),H9 1.2, H-7); δ_(F) (376 MHz.CDCl₃, CFCl₃) -68.2 ppm (s); δ_(C) (100 MHz, CDCl₃, Me₄ Sl) 117.3 ppm(d, J 35.1,C-6a), 122.2 (d, ³ J 3.8, C-7), 122.2 (s, C-1), 123.9 (d, ⁴ J1.9, C-10b), 124.2 (s, C-10), 126.5 (d, ⁶ J 2.3, C-2), 127.9 (s, C-9),128.7 (d, ⁴ J 1.6, C-4), 129.4 (s, C-3), 132.1 (s, C-8), 136.5 (d, ³ J7.2, C-10a), 141.5 (d, ³ J 17.9, C-4a), 158.1 (d, ¹ J 248.7, C-6); m/z(E1⁺) 197 (M⁺, 100%).

Example 13: Fluorination of quinoxaline

A solution containing quinoxaline (15.6 g), 120 mmol) and iodine (30.5g, 120 mmol) in CF₂ ClCFCl₂ (150 ml) was placed in a fluorinationapparatus fitted with a drying tube filled with soda lime. Elementalfluorine (165 mmol) as a 10% mixture in nitrogen was then passed throughthe stirred solution using narrow bore PTFE tubing at ca. 40 ml/min.After the fluorine had been added the solution was poured into 10%aqueous sodium metabisulfite solution (300 ml), neutralised with sodiumbicarbonate and continuously extracted with dichloromethane for 24hours. The organic extracts were dried and evaporated to an oil (13.6g). GC/MS analysis showed a 49% conversion of quinoxaline. The oil waspurified by column chromatography on silica gel using dichloromethane aseluant to give pure 2-fluoroquinoxaline as a pale yellow oil (5.30 g,62% based on 49% conversion); R_(F) 0.53; δ_(H) (200 MHz; CDCl₃ ; Me₄Si) 7.7 ppm (2H, m), 7.9 (1H, m), 8.1 (1H, m), 8.67 (1H, d, J_(H),F 7.9,H-3); δ_(F) (250 MHZ; CDCl₃ ; Me₄ Si) -75.1 ppm (s); δ_(C) (50.3 MHz,CDC13, Me₄ Si) 128.4 ppm (d, ⁴ J_(C),F 1.6, C-8), 129.4 (s, C-7), 129.45(s, C-6), 131.6 (s, C-5), 136.5 (d, ² J_(C),F 42.6, C-3), 139.72 (d, ³J_(C),F 10.9, C-8a), 141.52 (d ⁴ J_(C),F 1.8, C-4a), 156.74 (d, ¹J_(C-F) 256.0, C-2); m/z (E1⁺) 148 (M⁺, 100), 129 (20), 121 (12), 103(17), 76 (24), 50 (17); and 2,3-difluoroquinoxaline (0.27 g, 3%) as apale yellow solid; R_(F) 0.75; δ_(H) (400 MHz, CDCl₃, Me₄ Si) 7.79 ppm(2H, m, Ar-H), 7.99 (2H, m, Ar-H); δ_(C) (50 MHz, CDCl₃, Me₄ Si) 127.8(s, C-8), 130.4 (s, C-7), 130.4 (s, C-7), 138.4 (d d, ³ J_(C-F) 5.4,C-4a), 146.1 (d d, ¹ J_(C-F) 261.3,² J_(C-F) 39.5, C-2); δ_(F) (235 MHz,CDCl₃, CFCl₃) -82.8 ppm (s); m/z (E1+) 166 (M⁺, 100%), 139 (11).

We claim:
 1. A method of preparing a heterocyclic organic compoundhaving at least one fluorine substitute in the heterocyclic ring, themethod comprising reacting a heterocyclic compound with elementalfluorine in the presence of an elemental halogen other than fluorine. orin the presence of an interhalogen compound consisting of two differenthalogens.
 2. The method according to claim 1 wherein the heterocycliccompound includes a five or six membered substituted or unsubstitutedheterocyclic ring.
 3. The method according to claim 1 wherein theheterocyclic compound includes a six-membered aromatic ring containingone or more nitrogen atoms.
 4. The method according to claim 3 whereinthe heterocyclic compound is pyridine, pyrimidine, pyridazine, pyrazine,triazine, quinoline, isoquinoline, quinoxaline, quinazoline orbipyridine.
 5. The method according to claim 1 wherein the other halogenis selected from one or more of I₂, Br₂ and Cl₂.
 6. The method accordingto claim 1 wherein the elemental fluorine is delivered to theheterocyclic compound in an inert gas.
 7. The method according to claim1 wherein the heterocyclic compound is contained in an organic solventwhich also contains the other halogen, fluorine being passed into theorganic solvent.
 8. The method according to claim 7 wherein the organicsolvent is a fluorinated organic solvent.
 9. The method according toclaim 1 wherein the heterocyclic compound is reacted with elementalfluorine in the presence of a base.
 10. The method according to claim 9wherein the base is triethylamine, tributylamine, N-methylpiperidine,sodium fluoride or potassium fluoride.
 11. A method of preparing aheterocyclic organic compound having at least one fluorine substitute onthe heterocyclic ring, the method comprising reacting a heterocycliccompound with elemental fluorine in the presence of one or more of I₂,Br₂, Cl₂, or an interhalogen compound consisting of two differenthalogens, wherein the heterocyclic compound is a five or six memberedsubstituted or unsubstituted heterocyclic aromatic ring, and thereaction is performed in the presence of a base.
 12. The methodaccording to claim 3, wherein the ring is attached or benzofused to oneor more other aromatic rings.
 13. A product produced by the method ofclaim
 1. 14. A product produced by the method of claim
 11. 15. Themethod of claim 11, wherein the interhalogen compound is iodinemonobromide or iodine monochloride.
 16. The method of claim 1, whereinthe method comprises preparing a heterocyclic organic compound having atleast one fluorine substitute on a carbon atom in the heterocyclic ring.